CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

Lone-Star Tick Bite of the

We report 2 separate occurrences of lone-star tick bite to the conjunc- tiva. Both occurred within a 100- mile radius during the summer of 2000. A search of the literature yielded 2 reports of conjunctival tick bite.1,2 In one of these, the tick was removed with difficulty using a cot- ton-tipped applicator. We propose a simple, yet effective, method of re- moval.

Case Reports. Case 1. On July 9, 2000, a 5-year-old girl was evalu- Patient with Amblyomma americanum tick attached to conjunctiva temporally in the right eye. Magnified view illustrates leg (arrow) of tick. ated by her physician for an uniden- tified “spot” on her right eye. A tick and the surrounding area of ery- mon name for Amblyomma ameri- transmitted to humans by this tick thema were identified in the con- canum. The life cycle is composed of vector. In 1943, extraction of spot- junctiva temporally in the right eye the egg, larva, nymph, and adult ted fever rickettsia from an A ameri- (Figure). The remainder of the ocu- stages of development. The egg canum nymph was reported.3 Ambly- lar examination findings were nor- hatches into a 6-legged larva (“seed” omma has also been demonstrated to mal. Following referral to Arkansas tick), which attaches to a host and be a carrier of tularemia and an ery- Children’s Hospital (Little Rock), feeds. The larva then drops off the thema migrans–like rash illness simi- conscious sedation with ketamine host and metamorphoses into an lar to Lyme disease.4 As a known car- and midazolam allowed the com- 8-legged nymph. The nymph reat- rier of a number of diseases, A plete removal of the tick and a small taches to feed and later metamor- americanum poses a threat to hu- amount of the surrounding conjunc- phoses into an adult. The adult is dif- mans. It probably accounts for most tiva with forceps and Westcott scis- ferentiated into male and female. tick infestations in the United States, sors. Two weeks later, a follow-up The distinctive morphological especially in the south central states.5 telephone call revealed the patient to features of the species of Ambly- Complete removal is thought to be doing well, having been seen twice omma were described by G. Neu- lessen the potential for transmis- by her personal ophthalmologist. mann in 1896.3 The female tick is sion.6 Case 2. On August 8, 2000, a larger than the male counterpart. On As activities move to the out- 2-year-old girl was seen in the emer- the scutum, or dorsal hard plate, of doors during the summer months, gency department for evaluation of both the male and female are inter- tick bites, especially on exposed ar- tick bites. An ocular foreign body mittent white spots, hence the name eas of the body, may occur even af- prompted an ophthalmological con- “lone-star tick.” These spots are typi- ter a short time in wooded areas. At sultation and identification of a tick cally more prominent on the fe- least 4 hours of tick attachment are attached to the conjunctiva of her left male than on the male. The female thought to be necessary for spotted eye. Conscious sedation with ket- can have red and green markings in fever rickettsia transmission in hu- amine and midazolam allowed re- addition. mans.7 Preventive measures in- moval of the tick and surrounding A americanum is known to be a clude complete removal of the tick; conjunctiva with forceps and West- transmitter of diseases to domestic care must be taken not to leave cott scissors. One week later, there animals and to humans. Published re- mouth parts in the skin or to divide was no sign of infection or other ab- ports by Maria Maver (1911) of the tick’s body. Residual crushed tis- normality. Rocky Mountain spotted fever rick- sue and feces can also transmit dis- ettsia transmission by A america- ease. In the past, to avoid rupture or Comment. The lone-star tick, iden- num in guinea pigs led to the hypoth- incomplete removal of the tick, lin- tified in these 2 cases, is the com- esis that spotted fever could be dane shampoo, deodorized kero-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 sene, ether, or iodine were used.8,9 A B Since the tick bites we report in- volved the conjunctiva, mechani- cal extraction was the procedure of choice. We add our cases of con- junctival tick bite to the literature with a suggested method for re- moval.

Monica C. Love, BA Little Rock, Ark Lucas Platt, MD Rogers, Ark Christopher T. Westfall, MD Little Rock C D This work was supported in part by an unrestricted grant from Research to Prevent Blindness, New York, NY. Corresponding author: Chris- topher T. Westfall, MD, 4301 W Markham, Mail Slot 523, Little Rock, AR 72205 (e-mail: westfallchristopher @exchange.uams.edu).

1. Bode D, Speicher P, Harlan H. A seed tick infes- Figure 1. A, View of the anterior segment of the right eye shows microphthalmos with a cyst. B, View tation of the conjunctiva: Amblyomma america- of the anterior segment of the left eye shows and iridocorneal adhesion. C, Computed num larva. Ann Ophthalmol. 1987;19:63-64. tomography reveals solid masses in both kidneys (arrows) and medullary extension that consists 2. Jensen AL, Snow LR, Clifford CM. Spinose ear of a hypovascular component in the right kidney. D, Histopathologic findings from the resected tumor tick, Otobius megnini, attached to the conjunc- show a predominance of blastemal cells without epithelial components. The blastema is arranged in a tiva of a child’s eye [letter]. J Parasitol. 1982;68: serpiginous pattern and is sharply circumscribed from the surrounding stromal elements 528. (hematoxylin-eosin, original magnification ϫ25). 3. Cooley RA, Kohls GM. The genus Amblyomma (Ixodidae) in the Unites States. J Parasitol. 1944; 30:77-111. Wilms tumor gene (WT1) and the had predominantly blastemal cells 4. Kirkland KB, Klimko TB. Erythema migrans- like rash illness at a camp in North Carolina: a gene (PAX6) loci (MEM, (Figure 1D). The child also had un- new tick-borne disease? Arch Intern Med. 1997; No. 194070). We report a case of descended testes and mental retar- 157:2635. atypical WAGR syndrome with an- dation. Analysis of G-banded pro- 5. Chandler AC, Clark PR. Introduction to Parasi- tology. 10th ed. New York, NY: John Wiley & terior segment anomaly and mi- metaphase chromosomes identified Sons Inc; 1961:570-579. crophthalmos. deletion of chromosome 11p13- 6. Busvine JR. Discovery of unsuspected dangers. 15.1 in 1 allele (Figure 2). Chro- In: Disease Transmission by Insects: Its Discov- ery and Ninety Years of Effort to Prevent It. New Report of a Case. A 1-month-old boy mosomal analysis and physical find- York, NY: Springer-Verlag; 1993:82. had microphthalmos bilaterally. A ings were compatible with WAGR 7. Benenson AS, ed. Tick-borne rickettsiosies. In: Control of Communicable Diseases in Men. 14th microcornea with a corneal cyst in syndrome, but the ocular findings ed. Springfield, Va: American Public Health As- the right eye (axial length, 14.4 mm) differed substantially. sociation; 1985:329. (Figure 1A) and corneal opacity 8. Jones, BE. Human “seed tick” infestation: Am- blyomma americanum larvae. Arch Dermatol. and absent anterior chamber in the Comment. Since the PAX6 gene was 1981;117:812-818. left eye (axial length, 21.0 mm) (Fig- identified as a candidate gene for an- 9. Knight KL, Bryan DE, Taylor CW. Studies on the ure 1B) seemed to be part of an an- iridia, numerous mutations of 11p13 removal of embedded lone star ticks, Ambly- omma americanum. J Econ Entomol. 1962;55:273- terior segment anomaly that in- have been reported in patients with 276. cludes the Peter anomaly. The aniridia. Studies have identified Pax6 vitreous cavities and posterior seg- mutations in numerous ocular ments were normal. We examined anomalies, including the Peter the right eye with a small contact anomaly, congenital , and fo- A Case of Atypical WAGR and light stimuli and obtained a nor- veal hypoplasia.1 In situ hybridiza- Syndrome With Anterior mal response on the electroretino- tion and immunohistologic exami- Segment Anomaly and gram and in the left eye a subnor- nation identified multiple functions Microphthalmos mal response, suggesting retinal of the gene; the gene moves from the dysfunction. Wilms tumors devel- anterior to the posterior segments of Wilms tumor, aniridia, genitouri- oped bilaterally when the patient was the eye throughout development. nary anomalies, and mental retar- 3 years old (Figure 1C). Because of Therefore, it is not surprising that dation (WAGR syndrome) are a large tumor, we resected the right ocular anomalies other than an- caused by the deletion of chromo- kidney; the left kidney underwent iridia result from deletion of 11p13. some 11p13, which includes the . The resected tumor Two other patients were described

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 matory retinal disorder, typically ob- served in young patients, that is P15.4 Breakpoint (P15.1) P15.2 characterized by unilateral visual loss (p) and the presence of small, punc- P14.3 tate, yellow-white lesions that in- P14.1 P12 volve the outer . In addition to Breakpoint (P13) P11.12 Centromere reduced central visual acuity, pa- tients usually experience photop- sias and in the affected eye. A characteristic granular appear- ance may be observed in the macula (q) as well.1 Patients usually recover good visual acuity with disappear- ance of the outer retinal lesions Normal 11p(del) within 4 to 8 weeks of initial exami- nation, although subjective difficul- ties with vision may persist. Bilat- Figure 2. The G-banded prometaphase chromosomes show deletion of chromosome 11p13-15.1. The (p) indicates the short arm of the chromosome; (q), the long arm. eral involvement, recurrence, and delayed choroidal neovasculariza- tion can occur, but are infre- previously: a 2-month-old boy with these other factors and manifest cor- quent.2,3 Although the cause of a Peter anomaly and deletion of neal opacity, iridocorneal adhe- MEWDS is unknown, the presence 11p13 who did not have Wilms tu- sion, and microphthalmos. of elevated serum immunoglobulin mor2 and a 6-day-old boy with a Pe- levels4 and the description of ter anomaly and Wilms tumor in Eriko Kawase, MD MEWDS following a booster vacci- whom chromosomal analysis was Kiyoshi Tanaka, MD nation for hepatitis B virus5 suggest not undertaken.3 A 3-month-old boy Toshirou Honna, MD an immune basis for this disorder. with duplication of 11p13 had mi- Noriyuki Azuma, MD Immunization with inacti- crophthalmia.4 Genetically similar Tokyo, Japan vated hepatitis A virus vaccine mice with multiple copies of Pax6 (HAVV) is an effective means of pre- have a microphthalmic pheno- venting infection with hepatitis A, 5 The authors have no proprietary in- type, indicating gene dosage af- terest in any aspect of this report. a virus typically transmitted by con- fects normal function. Corresponding author: Noriyuki taminated water or food, particu- PAX6 mutations in aniridia are Azuma, MD, Department of Ophthal- larly shellfish. Currently, HAVV is usually nonsense, frameshift, or mology, National Children’s Hospi- recommended for travelers to de- splicing errors in 1 allele, which re- tal, 3-35-31 Taishido, Setagaya-ku To- veloping countries, children in en- sult in a truncated protein, thus, hap- kyo, 154-8509 Japan (e-mail: nazuma demic areas, people with chronic loinsufficiency of the gene prod- @nch.go.jp). liver disease, homosexual males, and ucts causes the aniridia phenotype, injection drug users. Nearly 6 mil- while few mutations in the Peter 1. Medical Research Council Human Genetics Unit. lion vaccine doses have been given anomaly are missense1. However, The human PAX6 allelic variant database Web site. in the United States during the past Available at: http://www.hgu.mrc.ac.uk/Softdata/ missense mutations recently found PAX6. Accessibility verified July 18, 2001. 2 years, and a recent safety review in patients with aniridia produce an- 2. Hanson IM, Fletcher JM, Jordan T, et al. Muta- showed few vaccine-associated ad- tions at the PAX6 locus are found in heterog- other route of haploinsufficiency. eneous anterior segment malformations includ- verse events, the most serious of Thus, the relation between PAX6 ing Peters’ anomaly. Nat Genet. 1994;6:168-173. which were hematologic or immu- gene dosage and phenotypic mani- 3. Eiferman RA. Association of Wilms’ tumor with nologic in nature, including vascu- Peters’ anomaly. Ann Ophthalmol. 1984;16:933- festations is still controversial. Af- 934. litis, thrombocytopenia, and auto- fected individuals in a pedigree with 4. Aalfs CM, Fantas JA, Wenniger-Prick LJJM, et immune hemolytic anemia.6 Our aniridia who had the same PAX6 mu- al. Tandem duplication of 11p12-11p13 in a child case represents the first reported with borderline development delay and eye. Am tations have wide phenotypic varia- J Med Genet. 1997;73:267-271. ophthalmic complication follow- tions. Because the PAX6 gene is in- 5. Schedl A, Ross A, Lee M, et al. Influence of PAX6 ing HAVV. gene dosage on development: overexpression fluential in numerous ocular tissues causes severe eye abnormalities. Cell. 1996;86: throughout development, pheno- 71-82. Report of a Case. A previously types may be reflected modifiers un- healthy, 30-year-old, white man linked to the PAX6 gene cascade, co- complained of 36 hours of worsen- factors of PAX6, or environmental ing vision in his left eye, which he conditions. Although aniridia and Multiple Evanescent White described as a steadily enlarging, anterior segment anomalies includ- Dot Syndrome Following shimmering gray cloud over his cen- ing the Peter anomaly are distinct Hepatitis A Vaccination tral vision. Medical history was no- clinical entities, in our patient, an- table for a hepatitis A booster vac- iridia resulting from deletion of one The multiple evanescent white dot cination administered 13 days before copy of PAX6 may be modified by syndrome (MEWDS) is an inflam- initial examination.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 A B C

A, Color fundus photograph of the left eye at initial examination showing multiple, faint, yellow-white lesions that affected the outer retina (arrows). B, A higher-power color photograph of the left fundus showed a shallow serous macular detachment that produced retinal striae. C, Humphrey visual field testing showed an enlarged blind spot and decreased foveal sensitivity.

On examination, best-cor- nation, vision remained 20/20 for pathogenesis of acute posterior mul- rected visual acuity was 20/20 in the each eye and retinal examination re- tifocal placoid pigment epitheliopa- right eye and 20/25-2 in the left eye. sults were normal, although subjec- thy,7 which, like MEWDS,5 has been A relative afferent pupillary defect tive persisted in the af- observed following inactivated hepa- and decreased color vision were pres- fected eye. titis B vaccination.8 ent in the left eye. Examination of the left posterior segment dis- Comment. We present the first case, Laura Fine, MD closed mild edema, a shal- to our knowledge, of MEWDS fol- Andrew Fine, MD, MPH low serous macular detachment, and lowing a booster HAVV. Our pa- Emmett T. Cunningham, Jr, MD, PhD, multiple, faint, yellow-white le- tient sought care 13 days after the MPH sions that affected the outer retina vaccine because of unilateral loss of San Francisco, Calif temporal to the fovea (Figure, A-B). vision, photopsias, an enlarged blind The results of examination of the spot, optic disc edema, and mul- This work was supported in part by a right posterior segment were unre- tiple yellow-white dots at the level Career Development Award from Re- markable. A Humphrey 30-2 visual of the outer retina, all findings that search to Prevent Blindness Inc, New field test showed marked enlarge- are consistent with the diagnosis of York, NY (Dr Cunningham). ment of the blind spot (Figure, C) MEWDS. Symptoms, visual acuity, Corresponding author: Emmett and decreased foveal sensitivity. A visual field changes, and fundus ab- T. Cunningham, Jr, MD, PhD, MPH, fluorescein angiogram showed late normalities all returned to normal The Pearl and Samuel J. Kimura Ocu- leakage from the disc and faint late within 6 weeks. lar Immunology Laboratory, The hyperfluorescence of the outer reti- The cause of MEWDS is un- Francis I. Proctor Foundation, UCSF nal lesions. known, although both infectious and Medical Center, San Francisco, CA Three days after the onset of immune-mediated origins have been 94143-0944 (e-mail: emmett 1 symptoms, vision decreased to 20/40 proposed. Jampol et al, in the origi- [email protected]). in the affected eye, and the dis- nal description of this syndrome, re- crete, yellow-white outer retinal ported an antecedent flulike illness 1. Jampol LM, Sieving PA, Pugh D, Fishman GA, Gilbert H. Multiple evanescent white dot syn- spots were more numerous and pro- in 50% of patients. Others, in con- drome, I: clinical findings. Arch Ophthalmol. nounced. At 10 days, the visual acu- trast, have cited the presence of in- 1984;102:671-674. ity remained 20/40, the left afferent creased levels of circulating immu- 2. Aaberg TM, Campo RV, Joffe L. Recurrences and bilaterality in the multiple evanescent white dot pupillary defect had disappeared, the noglobulins in the acute phase of syndrome. Am J Ophthalmol. 1985;100:29-37. blind spot had decreased in size, and MEWDS4 and the occurrence of 3. Callanan D, Gass DM. Multifocal choroiditis and choroidal neovascularization with the multiple a second posterior segment exami- MEWDS following hepatitis B vac- evanescent white dot syndrome and acute idio- 5 nation disclosed persistent, al- cination in support of an immune pathic blind spot enlargement syndrome. Oph- though milder, optic disc edema, basis for this disorder. Although it thalmology. 1992;99:1678-1685. 4. Chung Y, Yeh T, Liu J. Increased serum IgM and with partial resolution of the macu- is possible that the occurrence of vi- IgG in the multiple evanescent white dot syn- lar serous detachment and disap- sual symptoms following HAVV was drome. Am J Ophthalmol. 1987;104:187-188. pearance of the outer retinal spots. coincidental, this association ob- 5. Baglivo E, Safran AB, Borruat F. Multiple evanescent white dot syndrome after hepatitis Six weeks after initial examination, served in our patient would seem to B vaccine. Am J Ophthalmol. 1996;122:431- the patient’s vision had returned to support the role of an immune 432. 6. Niu MT, Salive M, Krueger C, Ellenberg SS. Two- 20/20 and the optic disc edema and mechanism in the pathogenesis of year review of hepatitis A vaccine safety: data serous detachment had completely MEWDS, particularly since hepati- from the Vaccine Adverse Event Reporting Sys- resolved. Subsequent Humphrey vi- tis A vaccination utilizes inacti- tem (VAERS). Clin Infect Dis. 1998;26:1475- 1476. sual field examination results were vated virus. An immune mecha- 7. Park D, Schatz H, McDonald HR, Johnson RN. normal. One year after initial exami- nism has also been implicated in the Acute multifocal posterior placoid pigment epi-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 theliopathy: a theory of pathogenesis. Retina. ulcer (Figure 1). A biopsy speci- Recombinant human platelet– 1995;15:351-352. 8. Brezin AP, Massin-Korobelnik P, Boudin M, men of the area demonstrated chronic derived growth factor BB is in- Gaudric A, LeHoang P. Acute posterior multi- inflammatory changes. The ulcer was volved in regulation of all phases of focal placoid pigment epitheliopathy after hepa- treated with hydrogen peroxide normal wound healing. It is either titis B vaccine. Arch Ophthalmol. 1995;113:297- 300. soaks, wet-to-dry dressings twice a synthesized or released from all cell day, and discontinued use of the pros- types involved in the healing pro- thesis (as allowed). The prosthesis cess.2,3 Both rh-PDGF-BB and other 0.01% Becaplermin Gel was refitted to minimize the pres- growth factor levels have been found sure at the orbital apex. A course of to be reduced in chronic, nonheal- for the Treatment topical antibiotic cream was also ap- ing wounds.2 Exogenous adminis- of a Chronic Orbital Ulcer plied. The ulcer, however, did not re- tration of rh-PDGF-BB in the form of After Exenteration solve for 15 months. Discharge was 0.01% becaplermin gel promotes not present and cultures were not ob- wound healing and was found to be Chronic orbital epithelial defect is tained. Treatment was then initi- effective for the treatment of dia- a rare complication that occurs af- ated with 0.01% topical becapler- betic foot ulcer and pressure ulcers ter exenteration. Skin grafts, rota- min gel daily, which was the only in multicenter, double-blind, pla- tion flaps, or free flaps are the tra- modification in the treatment regi- cebo-controlled trials.4 It is cur- ditional surgical means to correct men. The ulcer gradually decreased rently the only growth factor ap- such abnormalities. We describe a in size and was completely healed af- proved by the Food and Drug case of a chronic orbital epithelial de- ter 3 weeks (Figure 2). Use of the Administration for the treatment of fect after exenteration refractory to gel was discontinued a week later chronic diabetic foot ulcers. conventional treatment that re- without a tapering dose. No recur- This is the first reported case, to solved after being treated with 0.01% rence had occurred with a fol- our knowledge, of clinical use of topical becaplermin gel (recombi- low-up period of 12 months. 0.01% becaplermin gel (Regranex) in nant human platelet–derived growth the ophthalmic literature and sug- factor BB [rh-PDGF-BB] or Re- Comment. Chronic epithelial de- gests that this may be a powerful tool granex [Ortho-McNeil Pharmaceu- fects after exenteration have been de- in the treatment of chronic epithe- ticals Inc, Raritan, NJ]). scribed after radiation to the ,1 lial defects in oculoplastic surgery. after socket infection, and with dia- The Food and Drug Administra- Report of a Case. A 57-year-old Af- betes (as occurred in our patient). tion, however, has not yet approved rican American patient with a his- Skin grafts in these conditions have becaplermin for treatment of condi- tory of hypertension, seizures, and a high chance of failure because of tions other than diabetic foot ulcers. diabetes underwent a subtotal exen- compromised blood supply. A tem- Appropriate caution must be exer- teration with placement of a full- poralis rotation muscle flap offers a cised by physicians who choose to use thickness skin graft for primary or- good chance of cure but requires ad- this medication. bital . The orbital defect ditional surgery and may deform the healed slowly for several weeks. A temporalis fossa region. Free flaps re- Iftach Yassur, MD year later the patient underwent sult in scarring and deformity of the Marc J. Hirschbein, MD placement of craniofacial orbital im- donor site and neck area, where the James W. Karesh, MD plants for retention of an orbital pros- microvascular anastomosis is per- Baltimore, Md thesis. Following this procedure, she formed. Local treatment with agents developed an ulcer at the apex of the that promote wound healing is there- socket that measured 15ϫ4 mm with fore the most simple and cost- The authors have no commercial, pro- elevated edges and what appeared to effective treatment when taking into prietary, or financial interest in the be granulation tissue at the base of the account the cost of surgery. product mentioned in the article.

Figure 1. The socket of the left eye before treatment with becaplermin. Figure 2. The same area 3 weeks after treatment with becaplermin. A15ϫ4-mm ulcer is present at the apex of the orbit. The 2 metal implants that hold the orbital prosthesis are seen at the roof of the orbit.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Corresponding author: James W. tumors can show dramatic enlarge- 20/20 OS (pseudophakic eye). Intra- Karesh, MD, Department of Ophthal- ment without undergoing malig- ocular pressure readings were nor- mology, Krieger Eye Institute, Sinai nant transformation. mal. In the nasal aspect of the left Hospital of Baltimore, 2411 W Belve- The pigment epithelial layers of was a black lesion that spared the pu- dereAve,Baltimore,MD21215(e-mail: the eye often undergo reactive hy- pillary margin and extended to in- [email protected]). perplasia but true neoplasia of ocu- volve the base of the iris between the lar pigment epithelia is rare.1-4 On oc- 8:30- and 10-o’clock meridians 1. Savar DE. High-dose radiation to the orbit: a cause of skin graft failure after exenteration. Arch casion, however, true neoplasms can (Figure 1). The mass appeared to be Ophthalmol. 1982;100:1755-1757. develop from the pigment epithelia pushing anteriorly through the iris 2. Bennett NT, Schultz GS. Growth factors and 5-7 wound healing: part II: role in normal and of the iris, , and retina. stroma from the ciliary body but it did chronic wound healing. Am J Surg. 1993;166: Tumors of the pigment epithelium not seem to arise from or infiltrate the 74-81. generally are benign or low-grade stroma. Gonioscopy showed that the 3. Kiritsy CP, Lynch AB, Lynch SE. Role of growth factors in cutaneous wound healing: a review. malignancies and have no known lesion obscured a view of the angle Crit Rev Oral Biol Med. 1993;4:729-760. tendency to metastasize. However, structures and there was fine pig- 4. Wieman TJ, Smeil JM, Su Y. Efficacy and safety they can grow slowly and can be lo- ment dusting in the angle inferiorly. of a topical gel formulation of recombinant 5-7 human platelet–derived growth factor BB (be- cally invasive. We report a clini- Ultrasound biomicroscopy results re- caplermin) in patients with chronic neuro- copathologic correlation of an ad- vealed ciliary body thickening by the pathic diabetic ulcer: a phase III randomized pla- cebo-controlled double-blind study. Diabetes enoma of the ciliary body pigment mass and transillumination dis- Care. 1998;21:822-827. epithelium that secondarily in- closed a shadow that extended across vaded the iris and developed into a the pars plicata for 1 mm into the pars sizable intraocular mass. plana. The favored diagnosis was ad- Progressive Growth of enoma of the ciliary body pigment Benign Adenoma of the Report of a Case. In 1993, a 70- epithelium with secondary exten- Pigment Epithelium of the year-old woman was found on rou- sion through the iris. Because of her tine ocular examination to have an age and good visual acuity, it was Ciliary Body early cataract in her left eye. At that elected to continue to follow the pa- A 77-year-old woman underwent iri- time, her irides were normal and no tient conservatively. docyclectomy for a progressively en- pigmented lesions were noted. In In 1998, the lesion was first larging black mass that apparently 1995, the cataract had progressed noted to be displacing the intraocu- originated in the ciliary body and sec- and a small pigmented lesion was lar lens. In 1999, the patient’s visual ondarily invaded the iris of her pseu- first noticed in her left iris. This was acuity had decreased to 20/40 OS and dophakic left eye. At the time of sur- interpreted as a melanocytic nevus. the intraocular lens appeared to be gery, the tumor was adherent to the In 1996, the cataract had shown fur- covered by fibrous tissue in the quad- intraocular lens, which was re- ther progression and successful cata- rant of the tumor. An episcleral sen- moved along with the mass. Histo- ract extraction with placement of a tinel blood vessel had developed over pathologically, the tumor was com- posterior chamber intraocular lens the tumor and the angle pigmenta- posed of islands and cords of benign was performed. Two years later, the tion inferiorly had become denser. By pigment epithelial cells that were iris lesion had shown no convinc- 2000, the iris component of the le- separated by vascularized fibrous ing change, but suspicion of pos- sion had become larger (Figure 2) connective tissue. The diagnosis was sible melanoma prompted referral to and ultrasonography showed the adenoma of the ciliary body pig- the service. ciliary body component of the lesion ment epithelium with secondary in- At the time of our initial evalu- to be 6 mm thick. With transillumi- vasion of the iris. This case under- ation in 1997, the corrected visual nation, the lesion measured 7ϫ7mm scores the fact that benign intraocular acuity was 20/20 OD (phakic eye) and in diameter and extended more pos-

Figure 1. In 1997, the iris component of the lesion appeared as a black mass Figure 2. In 2000, the iris component of the lesion was slightly larger. in the nasal aspect of the iris. Transillumination and ultrasonography results revealed more pronounced ciliary body involvement posteriorly. The has been dilated pharmacologically.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Figure 3. Gross appearance of the resected lesion shows the black mass (to Figure 5. The tumor is composed of islands and cords of deeply pigmented the left) with a base (bottom). There is a firm attachment of the black epithelial cells with connective tissue stroma (hematoxylin-eosin; original mass to the intraocular lens (to the left). magnification ϫ200).

Figure 4. Pigmented mass with a section of normal iris adjacent to the lesion Figure 6. Bleached section showing bland cells with uniform nuclei (hematoxylin-eosin; original magnification ϫ10). (bleached, hematoxylin-eosin; original magnification ϫ200).

teriorly into the pars plana, almost duct formation. The melanin gran- til recently, they were often misdiag- reaching the ora serrata. ules in the cytoplasm were large and nosed clinically as malignant mela- Because of the progressive en- generally spherical in configuration, noma. In our case, the diagnosis was largement, the mass was resected by resembling those seen in the normal suspected clinically because of the a partial lamellar iridogoniocyclo- pigment epithelium. Bleached sec- black color of the lesion. Tumors of choroidectomy.8 Firm adherence of tions showed that the tumor nuclei the pigment epithelium tradition- the mass to the intraocular lens made were generally round or oval with ally have been considered to be rela- them inseparable, necessitating re- relatively well-dispersed chromatin tively dormant but a recent study re- moval of the lens along with the tu- and small to mildly conspicuous vealed that those in the ciliary body mor. Postoperatively, there was dif- nucleoli (Figure 6). The nuclei were can cause vitreous hemorrhage, sub- fuse vitreous hemorrhage, which only mildly pleomorphic and only 2 luxation of the lens, and secondary slowly resolved during 3 months mitotic figures were counted in 40 cataract,6 and that those of the reti- without the need for a vitrectomy. high-power fields. The posterior sur- nal pigment epithelium can be lo- Grossly, the black lesion had gical margin was free of tumor. Fi- cally invasive and cause exudative clear scleral margins. The mass par- brous tissue encompassed a groove in .7 Conversely, tu- tially encompassed the lens capsular the tumor that contained lens corti- mors of the iris pigment epithelium bag, which contained an intraocular cal and capsular remnants and a space tend to be more stationary and are lens (Figure 3). Microscopically, the that was occupied by the intraocular less likely to exhibit local invasion. In specimen consisted of a lamella of lens haptic in vivo. This was sur- a clinical series of 20 consecutive sclera on which rested a pigmented rounded by capsular fibrosis. There cases of adenoma of the iris pigment tumor that was passing through the was mild invasion of the ciliary body epithelium, only 2 required surgical thinned iris (Figure 4). The mass stroma by the tumor. The final diag- removal and 18 remained station- was composed of nests, cords, and is- nosis was adenoma of the ciliary body ary during the course of follow up.5 lands of intensely pigmented epithe- pigment epithelium with secondary The tumor in our patient was ini- lial cells that were separated by promi- iris invasion. tially suspected be an iris lesion but nent septa of vascularized fibrous detailed examination suggested that connective tissue (Figure 5). The Comment. Tumors of the ciliary body it probably originated in the pigment cords were solid without evidence of pigment epithelium are rare.6,9-13 Un- epithelium of the ciliary body. Docu-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 mentedgrowthofthetumorprompted Corresponding author and re- mented adenoma of the ciliary epithelium ex- amined by magnetic resonance imaging. Am removal and the diagnosis was con- prints: Jerry A. Shields, MD, Oncol- J Ophthalmol. 1995;120:679-681. firmed histopathologically. ogy Service, Wills Eye Hospital, 900 13. Rennie IG, Faulkner MK, Parsons MA. Ad- A remarkable histopathologic Walnut St, Philadelphia, PA 19107. enoma of the pigmented ciliary epithelium. Br J Ophthalmol. 1997;78:484-485. feature of the tumor reported here 1. Kurz GH, Zimmerman LE. Vagaries of the reti- is that it was composed predomi- nal pigment epithelium. Int Ophthalmol Clin. nantly of solid cords and tubules of 1962;2:441-464. tumor cells. These findings are more 2. Green WR. Retina. In: Spencer WH, ed. Oph- Extramedullary Myeloid thalmic Pathology: An Atlas and Textbook. 4th consistent with reported cases of ad- ed. Philadelphia, Pa: WB Saunders;1996:1312- Cell Tumor in enomas of the iris pigment epithe- 1313. an Elderly Man 5 3. Shields JA, Shields CL. Tumors and related le- lium. In contrast, tumors that arise sions of the pigment epithelium. In: Shields JA, from the ciliary body pigment epi- Shields CL. Intraocular Tumors: A Text and At- Extramedullary myeloid cell tumor thelium are usually characterized by las. Philadelphia, Pa: WB Saunders; 1992:438- (granulocytic sarcoma, chloroma) is numerous clear vacuoles and have 444. 4. Shields JA, Shields CL. Tumors of the retinal a rare cause of proptosis that can less connective tissue stroma.6 The pigment epithelium. In: Shields JA, Shields CL. masquerade as lymphoma. Proper tumor in our patient lacked such Atlas of Intraocular Tumors. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999:288- distinction between the two allows vacuoles. From a clinical stand- 292. appropriate radiation dosing. We point, however, the tumor ap- 5. Shields JA, Shields CL, Mercado G, Gunduz K, demonstrate in a 72-year-old man we peared to originate in the ciliary body Eagle RC Jr. Adenoma of the iris pigment epi- thelium: a report of 20 cases: the 1998 Pan- saw with , proptosis, bin- and to secondarily invade the iris. American Lecture. Arch Ophthalmol. 1999;117: ocular , and pain in the right The tumor reported here 736-741. eye that extramedullary myeloid cell showed progressive enlargement, 6. Shields JA, Shields CL, Gunduz K, Eagle RC Jr. Adenoma of the ciliary body pigment epithe- tumor may be treated with radia- secondarily invaded the iris, in- lium: the 1998 Albert Ruedemann Sr Memo- tion alone using as little as 450-rad duced the development of a sentinel rial Lecture, part 1. Arch Ophthalmol. 1999; 117:592-597. (4.5 Gy) applied in small fractions. blood vessel, and displaced and par- 7. Shields JA, Shields CL, Gunduz K, Eagle RC Jr. This approach spares the elderly pa- tially adhered to the intraocular lens. Neoplasms of the retinal pigment epithelium: tient from the general myelosup- Physicians should be aware that pro- the 1998 Albert Ruedemann Sr Memorial Lec- ture, part 2. Arch Ophthalmol. 1999;117:601- pression of chemotherapy. gressive growth of a ciliary body or 608. iris mass does not necessarily imply 8. Shields JA, Shields CL, Shah P, Sivalingam V. Report of a Case. An otherwise malignant transformation. Ancillary Partial lamellar sclerouvectomy forciliary body and choroidal tumors. Ophthalmology. 1991; healthy 72-year-old man developed measures such as gonioscopy, trans- 98:971-983. epiphora, proptosis, binocular diplo- illumination, and ultrasound bio- 9. Wilensky JT, Holland MG. A pigmented tu- mor of the ciliary body. Arch Ophthalmol. 1974; pia, and pain in his right eye over an microscopy are often necessary to de- 92:219-220. 8-month period. Ocular and medi- termine the size and extent of a ciliary 10. Chang M, Shields JA, Wachtel DL. Adenoma cal histories were noncontributory. body mass. Recognition of the char- of the pigmented epithelium of the ciliary body simulating a malignant melanoma. Am J Oph- Visual acuity was 20/50 OD and 20/40 acteristic features of adenoma of the thalmol. 1979;88:40-44. OS. External examination revealed ciliary body pigment epithelium 11. Lieb WE, Shields JA, Eagle RC, Kwa D, Shields right-sided hypoglobus, exophthal- should facilitate the diagnosis of this CL. Cystic adenoma of the pigmented ciliary epithelium: clinical, pathological and immu- mos, and a ruddy, red bulbar con- unusual tumor. nohistochemical findings. Ophthalmology. 1990; 97:1489-1493. junctiva associated with a large or- 12. Greenburg PB, Haik BG, Martin PC. A pig- bital mass that was firm to the touch Jerry A. Shields, MD Ralph C. Eagle, Jr, MD Carol L. Shields, MD Arun D. Singh, MD Philadelphia, Pa Paul F. Torrisi, MD Syracuse, NY

This research was supported by the Eye Tumor Research Foundation, Philadelphia, the Award of Merit in Retina Research, Houston, Tex (Dr J. A. Shields), the Macula Foundation, New York, NY (Dr C. L. Shields), and by the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathol- ogy, Wills Eye Hospital, Philadel- phia (Dr Eagle). We thank Anthony LaTessa, MD, and Richard A. Frio, OD, for their help Figure 1. When first seen for evaluation, the patient had right-sided hypoglobus, , and a in the management of the patient. ruddy, red bulbar conjunctiva.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 and the mass did not perform retro- pulsion, instead when pushed it was firm and moved back (Figure 1). Hertel exophthalmometry measure- ments were 23 mm OD and 13 mm OS with a base of 125 mm. Confron- tational fields were full. Ocular mo- tility was restricted in all fields of gaze in the right eye. Intraocular pressure was 21 mm Hg OD compared with 15 mm Hg OS. Slitlamp biomicroscopy revealed the conjunctiva of the right eye was severely congested and ex- panded by a solid, salmon-colored mass (Figure 2). Orbital computed tomogra- phy (Figure 3) revealed a homo- geneously enhancing mass in the re- gion of the right upper . The Figure 2. When first seen for evaluation, the conjunctiva of the patient’s right eye was severely congested mass molded to the lateral aspect of and expanded by a solid, salmon-colored mass. the , involved the tendinous in- sertion of the lateral rectus muscle, and extended to the intraconal space. A transconjunctival biopsy of the lesion was performed. Intraopera- tive touch preparations demon- strated a malignant hematolymphoid neoplasm. Portions of the tissue were placed in Zenker fixative and 10% buffered formalin for routine light mi- croscopy. Additional specimens were submitted fresh for flow cytometry and cytogenetics. Histopathological examination findings demonstrated a solid sheet of monomorphous, inter- mediate to large cells filling the con- junctival stroma. Individual cells showed a high nuclear-cytoplasmic ratio, with only a scant rim of eosino- philic cytoplasm. Nuclei were hyper- chromatic, irregularly contoured, and Figure 3. Orbital computed tomography with contrast. A homogeneously enhancing mass is contained central nucleoli and dis- demonstrated in the lid, conjunctiva, and orbit, molding to the lateral aspect of the globe. persed chromatin (Figure 4). On im- munohistochemical staining, the neo- plastic cells were reactive to CD45 (leukocyte common antigen), CD43, and lysozyme (Figure 5) but did not react with CD3 (pan T-cell) and CD20 (pan B-cell) markers. Flow cy- tometry confirmed the myeloid na- ture of the neoplasm, as demon- strated by expression of CD33 tumor cells and a subset of CD34 tumor cells (Figure 6A). There was an absence of CD5 and CD20 cells (Figure 6B). The pathological diagnosis was ex- tramedullary myeloid cell tumor. Systemic evaluation showed no lymphadenopathy and findings from the patient’s peripheral blood smear Figure 4. Tumor cells are discohesive with higher nuclear-cytoplasmic ratios. Round to irregular nuclear were normal. No other extramyelog- contours with prominent central nucleoli. enous deposits were found on meta-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 A B

Figure 5. A, CD45 stain. Diffuse, strong membrane positivity. Diaminobenzadine reaction product (original magnificationϫ100). B, Lysozyme stain. Positive staining in a majority of the tumor cells. Diaminobenzadine reaction product (original magnificationϫ100).

static workup. Therapy with 30 rad 104 104 (0.3 Gy) of orbital irradiation in 15

fractions was accomplished over a 103 103 3-week period. All signs and symp-

toms were eliminated by 1 month 102 102 CD5 PE (Figure 7). After 13 and again at CD33 PE 21 months, he reported no symp- 101 101 toms by telephone but declined to return for evaluation. 100 100 100 101 102 103 104 100 101 102 103 104 Comment. Extramedullary my- Time, y Time, y eloid cell tumor (granulocytic sar- Figure 6 A, Flow cytometry demonstrates a large majority of cells to be CD33 positive (upper half) and a coma, chloroma) is a rare tumor com- small subset to be CD34 positive (upper right quadrant). B, Flow cytometry demonstrates tumor cells fail posed of immature granulocytes.1,2 to reveal CD5 or CD20 reactivity. The disease may manifest in several different clinical settings. Most com- monly it occurs in childhood,1 and most often in combination with pre- existing acute myelogenous leuke- mia. It also occurs as a harbinger of acute myelogenous leukemia in non- leukemic patients. Less often, it has been reported in conjunction with myelodysplastic disorders or chronic myelogenous leukemia.3 The major- ity of nonleukemic patients with ex- tramedullary myeloid cell tumor will develop leukemia within a matter of months,4 but a delay of 16 years fol- lowing initial evaluation has been ob- served.3 The tumor is exceedingly rare in the elderly.5 Extramedullary sites of involve- ment are usually in extraocular tis- sues. Most commonly involved are bone, lymph nodes, periosteum, and Figure 7. One month status after . Initial signs seen at first evaluation are absent. skin.4 When ophthalmic manifesta- tions occur, they are usually or- bital.6 Signs and symptoms fre- Histopathological diagnosis of ment of lymphoma of the orbit and quently include pain, proptosis, extramedullary myeloid cell tumor ocular adnexa requires 2400 to 4000 chemosis, and epiphora. Com- may be difficult to ascertain on rou- rad (24-40 Gy) of total irradia- puted tomography frequently re- tinely processed tissue sections, and tion.8-10 Immunophenotyping tu- veals a homogeneous, well-defined it is often confused with malignant mor cells either by flow cytometry tumor that molds to surrounding lymphoma. The distinction is im- or immunohistochemistry is effica- bone.7 portant because successful treat- cious in differentiating these 2 en-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 tities. Extramedullary myeloid cell leukemic patient with isolated or- sarcoma or chloroma). Am J Ophthalmol. 1975; 80:975-990. tumors are positive for CD45 and bital extramedullary myeloid cell 2. van Veen S, Kluin PM. Granulocytic sarcoma CD43 and negative for other B-cell tumor, and it will spare the elderly (chloroma): presentation of an unusual case. and T-cell markers. In addition, they patient from the general myelosup- Am J Clin Pathol. 1991;95:567-571. 3. Meis JM, Butler JJ. Granulocytic sarcoma in non- usually show some degree of reac- pression that often accompanies che- leukemic patients. Cancer. 1986;58:2697- tivity with antibodies to lysozyme or motherapy. 2709. 11 4. Neiman RS, Barcos M. Granulocytic sarcoma: myeloperoxidase. By flow cytom- a clinicopathologic study of 61 biopsied cases. etry, tumor cells are CD33 positive Wade D. Brock, MD Cancer. 1981;48:1426-1437. and variably CD34 positive. Harry H. Brown, MD 5. Watkins LM, Remulla HD, Rubin PA. Orbital Christopher T. Westfall, MD granulocytic sarcoma in an elderly patient. Am Prognosis and treatment of ex- J Ophthalmol. 1997;123:854-856. tramedullary myeloid cell tumor is Little Rock, Ark 6. Davis JL, Parke DW, Font RL. Granulocytic sar- dependent on the presence or lack coma of the orbit: a clinicopathologic study. This work was supported in part by an Ophthalmology. 1985;92:1758-1762. of an associated leukemia or dyspla- 7. Jakobiec FA. Granulocytic sarcoma. AJNR sia,6 but in the absence of an asso- unrestricted grant from Research to Am J Neuroradiol. 1991;12:263-264. Prevent Blindness, Inc, New York, NY. 8. Jereb B, Lee H, Jakobiec FA. Radiation therapy ciated systemic malignancy, the of conjunctival and orbital lymphoid tumors. prognosis is indeterminate. In our Corresponding author and re- Am J Radiat Oncol Biol Phys. 1984;110:1013- case there was no identified associ- prints: Christopher T. Westfall, MD, 1019. Harvey and Bernice Jones Eye Insti- 9. Kennerdell JS, Flores NE, Harsock RJ. Low- ated malignancy. Treatment in such dose radiotherapy for lympoid lesions of the or- cases is not standardized. Fre- tute, Department of Ophthalmology, bit and ocular adnexa. Ophthal Plast Reconstr quently, chemotherapy and irradia- University of Arkansas for Medical Surg. 1999;15:129-133. Sciences, 4301 W Markham, Slot 523, 10. Smitt MC, Donaldson SS. Radiotherapy is suc- tion are used together and result in cessful treatment for orbital lymphoma. Int J Ra- a rapid response.2,5, Irradiation alone, Little Rock, AR 72205-7199. diat Oncol Biol Phys. 1993;26:59-66. 11. Traweek ST, Arber DA, Rappaport H, Brynes as in this case, may be efficacious in 1. Zimmerman LE, Font RL. Ophthalmic mani- RK. Extramedullary myeloid cell tumors. Am J the treatment of a systemically non- festations of granulocytic sarcoma (myeloid Surg Pathol. 1993;17:1011-1019.

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